A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Pharmacodynamic Biomarker p70S6K
研究概览
简要总结
Given the role of mTOR signaling and probable synergistic activity of combining sirolimus and metformin in patients with advanced solid tumors, the investigators hypothesize that:
- The combination of metformin plus sirolimus will result in reduction of p4EBP1, p70S6K and pAKT more than sirolimus alone in peripheral blood T cells (PBTC).
- The combination of metformin plus sirolimus will result in decreased levels of serum biomarkers including fasting insulin, C-peptide, glucose, triglycerides, LDH, IGF-1, IGF-1R, IGF-BP and leptin, but an increase in adiponectin in peripheral blood.
- Expression of active forms of AMPK, mTOR, PI3K, PTEN loss, AKT, LKB1, P62, LC3, and/or ULK1 in the tumor tissue (original pathology) will be predictive of response to combination therapy. This will be an exploratory hypothesis for this study.
- Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be mitigated by combining sirolimus with metformin.
- Metformin plus sirolimus will have promising anti-cancer activity and this activity will correlate with decreases in the above biomarkers. This will be an exploratory hypothesis for this study.
详细描述
Objectives:
This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and metformin therapy.
Primary Objective:
i. To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
Secondary Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Metformin XR
All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin.
干预措施: Metformin XR (Drug)
Metformin XR
All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin.
干预措施: Sirolimus (Drug)
Delayed Metformin
All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks.
干预措施: Delayed Metformin (Drug)
Delayed Metformin
All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks.
干预措施: Sirolimus (Drug)
结局指标
主要结局
Pharmacodynamic Biomarker p70S6K
时间窗: 28 days
To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
次要结局
- Pharmacodynamic Biomarkers p4EBP1 and pAKT(28 days)
- Tolerability - Full physical Exam(28 day cycles)
- Fasting Serum Glucose and Triglycerides(28 days)